The compound 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, also known as nitisinone or NTBC, was first disclosed as a herbicide (U.S. Pat. No. 5,006,158; U.S. Pat. No. 4,695,673; U.S. Pat. No. 5,668,089).
Nitisinone is used under the brand name Orfadin® for the treatment of hereditary tyrosinemia type I (HT-1), a rare paediatric disease. HT-1 is a genetic metabolic disorder that results from an inability to break down the amino acid tyrosine. Because of resulting liver failure and liver cancer, children with HT-1 rarely survive into their twenties without a liver transplant.
As disclosed in e.g. U.S. Pat. No. 5,550,165, nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase (HPPD), an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity.
Further, nitisinone has been described as being useful in the treatment of other disorders, such as Parkinson's disease (WO 2006/090117); depression (WO 2008/020150); restless leg syndrome (WO 2010/054273); and alkaptonuria (Sunwanarat, P. et al., Metabolism 54: 719-728, 2005). The use of nitisinone has also been disclosed in a method for enhancing phagolysosomal fusion following infection of a patient with a microorganism (U.S. patent application, publication No. 2010-0227936).
Oral administration of drugs is one of the preferred routes for treatment, because of its simplicity. While drugs are generally administered in the form of tablets or capsules, such administration may be less preferred, for example when the dosage has to be finely adapted to treated subject, or may be less convenient, for example in the case of paediatric or veterinary drugs. The liquid dosage form may then be an advantageous alternative.
Consequently, there is a need for stable liquid nitisinone compositions which are adapted for administration to paediatric patients and overcome the drawbacks with solid pharmaceutical compositions.